Abstract

Background With few exceptions, the prevalence, incidence and
morbidity risk of depressive disorders are higher in females than in males,
beginning at mid-puberty and persisting through adult life.

Aims To review putative risk factors leading to gender differences
in depressive disorders.

Method A critical review of the literature, dealing separately with
artefactual and genuine determinants of gender differences in depressive
disorders.

Results Although artefactual determinants may enhance a female
preponderance to some extent, gender differences in depressive disorders are
genuine. At present, adverse experiences in childhood, depression and anxiety
disorders in childhood and adolescence, sociocultural roles with related
adverse experiences, and psychological attributes related to vulnerability to
life events and coping skills are likely to be involved. Genetic and
biological factors and poor social support, however, have few or no effects in
the emergence of gender differences.

Conclusions Determinants of gender differences in depressive
disorders are far from being established and their combination into integrated
aetiological models continues to be lacking.

Epidemiological findings point to a female preponderance in prevalence,
incidence and morbidity risk of depressive disorders. Increased risk to
females varies by diagnostic subtypes and is substantial for major depression,
dysthymia, atypical depression and seasonal winter depression, although it
does not occur in bipolar disorder (but females predominate in rapid-cycling
and mixed-state episodes). Moreover, age is a crucial factor, and higher rates
of depression in females are detected at mid-puberty through adult life, as
opposed to a male preponderance until early adolescence. Finally, the female
preponderance is not ubiquitous and is limited, or even absent, in traditional
societies and in socially homogeneous samples
(Piccinelli & Gomez Homen,
1997). This paper aims to review putative risk factors leading to
gender differences in depressive disorders. For this purpose, artefactual and
genuine determinants will be considered separately
(Weissman & Klerman,
1977).

ARTEFACTUAL DETERMINANTS

Thresholds for caseness

At present, the definitions of depressive disorders remain arbitrary
because of the absence of clear markers or ‘natural’ thresholds in
symptom distribution. The tendency of females to report more depressive
symptoms than males might be responsible for their greater likelihood of
meeting criteria for a depressive disorder, even though males and females with
depressed mood report similar levels of subjective, social and occupational
impairment (Angst & Dobler-Mikola,
1984). Several studies have shown that a female preponderance in
rates of depression occurs at low symptom thresholds and becomes more
pronounced as the number of symptoms increases. Moreover, similar
relationships between levels of depression and occupational impairment have
been reported in males and females
(Kessler et al, 1993;
Fennig et al,
1994).

Measurement procedures

Clinical manifestations of depression differ by gender, with females more
often reporting disturbances of appetite and sleep, fatigue, somatic anxiety
and hypochondriasis (Frank et al,
1988; Young et al,
1990; Silverstein,
1999). Thus, the inclusion of gender-dimorphic items in rating
scales and diagnostic algorithms may influence depression rates. In fact,
gender differences in symptom profile tend to be limited in type and severity,
and gender-specific response patterns on rating scales for depression do not
seem fully to account for gender differences in levels of depression
(Steer et al, 1989;
Stommel et al,
1993).

Effect of recall

The issue of temporal stability in reporting mental disorders has received
direct attention in several studies, suggesting that passage of time greatly
affects accuracy of recall (Bromet et
al, 1986; Dohrenwend,
1989). No consistent gender-specific recall patterns have been
reported, which might result in an artefactual female preponderance in
depression rates. Indeed, females outnumber males even when depressive
episodes are assessed over short time periods preceding examination in order
to limit the recall bias. Also, there are no significant gender differences in
the temporal distribution of depressive episodes, no gender-by-time
interaction in the likelihood of reporting depressive symptoms or, even, a
better recall of past episodes in males
(Coryell et al, 1992;
Fennig et al, 1994).
A sophisticated approach based on longitudinal design and corroborative
witness reports, allowing for partial correction of the tendency of males to
forget or minimise previous episodes, found a trend for higher lifetime rates
of depression in females at the time of the emergence of gender differences in
social roles (Wilhelm & Parker,
1994; Wilhelm et al,
1997).

Course of illness

Gender differences in the course of depression, rather than in its
occurrence, might be responsible for the higher prevalence rates among
females. Findings are controversial: some studies report higher rates of
first-onset depression in females rather than a greater number, or longer
duration, of episodes (Kessler et
al, 1993; Wilhelm et
al, 1997); others show a female preponderance in recurrent
and chronic depression
(Stefànsson
et al, 1994; Bracke,
1998). In any case, the course of illness loses its relevance in
computing lifetime prevalence rates, which are consistently higher in females
than in males.

Differential mortality in males and females with depression has been also
considered but can hardly account for gender differences in depression, since
these appear at puberty through adult life and decrease in older cohorts, when
the differential effect of mortality is expected to be more pronounced.

Depression spectrum

Developmental pathways towards depression may differ by gender, with
females suffering from pre-existing anxiety disorders and males experiencing
more externalising disorders, such as alcoholism, antisocial personality and
drug misuse. In this regard, the concept of ‘depression spectrum
disease’ has been suggested to identify a specific gene-environment
interaction leading to depression in females and alcoholism in males. At
present, the evidence suggests that the above-mentioned disorders may share
genetic and environmental factors with depression but cannot be considered
simply as indirect manifestations of depression
(Cadoret et al, 1996;
Kendler et al, 1997;
Stallings et al,
1997; Dawson & Grant,
1998).

EXPLANATORY FACTORS

Several risk factors have been investigated. They are listed in
Table 1.

Familial environment and adverse experiences in childhood

Genetic studies have shown that environmental factors shared in families do
not substantially influence liability to major depression and do not
contribute to observed gender differences
(Kendler et al, 1995;
McGuffin et al,
1996). None the less, the role of familial environment cannot be
totally dismissed, because events occurring within families and not shared by
family members remain candidates. Familial factors may contribute to
vulnerability to depression in terms of personal attributes modulating the
response to life events, with no increased risk of illness in the absence of
such crises. Age and strictness of diagnostic criteria may be critical
variables, since depressive illness in children, as well as milder forms of
depression, seems to be largely related to unique or shared environmental
factors (Brown, 1996;
Farmer, 1996;
Harrington, 1996;
Silberg et al,
1999).

Much attention has been devoted to parental separation/divorce (with
resulting lack of child care in early years) and to the effects of physical
and sexual abuse in childhood as possible risk factors for depression in adult
life. Adverse experiences in childhood have been shown to increase the risk of
later depression through several pathways, including: biological mechanisms
(that is, long-term dysregulation of the
hypothalamic—pituitary—adrenal axis); personal vulnerability
(namely low self-esteem, helplessness, external locus of control, poor coping
strategies); adverse environmental factors (such as lack of social support,
low social status, ongoing difficulties like single parenthood or unplanned
pregnancy); and a depression episode in teenage years
(Kendler et al, 1993;
Bifulco et al, 1998;
Weiss et al, 1999).
However, gender differences in the association between adverse experiences in
childhood and adult depression have been poorly investigated. The available
evidence suggests that early traumatic experiences may be partly responsible
for a female preponderance in depression rates, since females are at greater
risk of certain events (such as sexual abuse) and seem to be more sensitive to
their depressogenic effects (Rodgers,
1994; Veijola et al,
1998).

Prior depression and anxiety disorders

Females are at greater risk of depression and anxiety disorders at earlier
ages than males, and this may partly account for their preponderance in rates
of adult depression. Among possible reasons accounting for the greater risk to
females and at earlier ages, psychological attributes such as neuroticism may
be key determinants, acting as vulnerability factors in response to life
events (Wilhelm et al,
1997).

Depressive episodes in childhood and adolescence, rather than those at
older ages, predict more episodes and longer duration of depression in adult
life and provide a strong link between adverse experiences in childhood and
adult depression (Kendler et al,
1993; Parker et al,
1997; Bifulco et al,
1998). Considerable attention has been devoted to the role of
anxiety. Using discrete-time survival models, Kessler et al
(1996) showed that the
associations between major depression and first onsets of other mental
disorders in the same year as depression were generally strong and persistent
over many years, and especially so for generalised anxiety. More recently,
Parker et al (1997)
assessed risk factors differentiating early-onset (that is, at an age younger
than 26 years) from late-onset depression and found that anxiety disorders
were more likely to precede early-onset than late-onset depression. Finally,
Breslau et al (1995)
showed that controlling for prior anxiety disorders reduced by more than 50%
the size of the estimated association between gender and depression.

Social roles and cultural norms

The identification of individuals at high risk for developing depression,
based on socio-demographic variables and data collected across different
countries and cultural groups, indicates that social roles and cultural
influences contribute to a female preponderance in depression rates.

Detailed reviews of epidemiological findings (Bebbington,
1996,
1998) suggest that marriage may
have detrimental effects in females, possibly due to gender-specific demands
posed by marriage and the resulting limited number of roles available to
females. Similar reasons may explain why looking after small children is
associated with greater risk of depression in females. Both home-making and
child care reduce the likelihood of females being in paid employment or put
additional responsibilities on those who are employed. Married females with no
paid employment have to rely for identity and self-esteem on the role of
housewife, a role that carries many frustrating elements and has been
increasingly devalued in modern societies. On the other hand, females entering
the job market face economic discrimination and job inequality along with role
overload and role conflict caused by concurrent primary responsibility for
household chores and child care. Although employment tends to have beneficial
effects on psychological well-being, these effects may be reduced or reversed
where there is role conflict and overload.

The ‘role strain’ hypothesis is unlikely to account entirely
for gender differences in depression. For example, despite significant
associations between emotional distress and role underload (in both genders)
or role overload (in females), in a representative sample of private
households in England, Wales and Scotland, gender differences in emotional
distress persisted after controlling for socio-economic status, number of
social roles and occupancy of traditional female caring and domestic roles
(Weich et al,
1998).

Life events

Stressful life events retain a substantial causal relationship with the
onset of depressive episodes (Kendler
et al, 1999). No clear evidence is available on the
differential role of life events in males and females, but the quality of
experience associated with life events may contribute to gender differences in
depression.

The assumption that females might be at higher risk of depression owing to
higher rates of adverse life events has received inconsistent support, with
some studies showing gender differences in the expected direction and others
finding similar levels of life events in males and females. In any case, the
excess of life events in females has not been found to account entirely for
their higher frequency of affective disorders
(Bebbington, 1996).

Older studies simply recorded the level of life events and did not assess
whether males and females differ in the meaning they attach to them. Craig
(1996) reported that
experiences of defeat, humiliation and entrapment were at the heart of
depressive episodes in males and females, although females were far more
likely to report such experiences, possibly because of their distinctive
social circumstances. Similarly, Wilhelm et al
(1998) found no gender
differences in frequency of life events or in anticipated impact of pleasant
and unpleasant events, whereas the actual impact of unpleasant events was
rated higher by females.

An increased risk of the onset of depression may reasonably be expected
when severe events occur in life domains to which individuals attach a strong
sense of value and commitment. Individuals with few overvalued goals and/or
lacking an intimate sense of perceived choice are at high risk since they are
left with few alternatives for self-definition and self-evaluation when their
main goals are threatened. Both of these situations are more likely for
females. Consistent with a role hypothesis, a study of couples reported that
the excess of depression onset among females following adverse life events was
entirely restricted to crises involving children, housing or reproductive
problems. This occurred among those couples with a clear gender difference in
the associated roles, resulting in increased responsibility of females in
these areas (Nazroo et al,
1997). These findings suggest that biological sex represents a
useful starting approach in research on gender differences in depression,
provided that the observed differences are then related to sociocultural roles
and norms by considering an individual's multiple social identities within his
or her current and biographical contexts.

Vulnerability and coping style

The role of adverse life events in producing depression is mostly mediated
through interaction with individual vulnerability, as expressed by personality
characteristics, attributional style and cognitive coping
(Brewin, 1996;
Hänninen & Aro, 1996). Familial aggregation of depressive episodes,
temperamental features such as low self-esteem, and life events suggest that
genetic factors may influence stable personal characteristics involved both in
vulnerability to depression and in exposure to high-risk environments
(McGuffin et al,
1988; Kendler et al,
1993,
1998).

Bebbington (1996) has
reviewed the evidence on the effects produced by expectations and
attributional style in depression. Expectations of negative outcomes and of
helplessness lead to hopelessness, which may progress into depression. The
experience is moderated by causal attributions to events, by evaluation of
their consequences and by the related inferences about the self. Individuals
at risk of depression have been described as characterised by globality (that
is, failure is related to factors applying across a variety of situations);
stability (namely, factors responsible for failure are unlikely to change over
time); and internality (where the individual regards himself or herself as
relatively incompetent). At present, there is insufficient support for the
notion that the cognitive characteristics of females are more consistent with
a depressive attributional style than those of males.

According to Nolen-Hoeksema
(1987), the increased
vulnerability of females to depression is mainly related to gender differences
in coping with an initial lowering of mood, rather than in personality
characteristics of assertiveness and passivity, which may predispose to
depression. Specifically, males tend to distract themselves from their mood by
engaging in physical or instrumental activities, whereas females are less
active and ruminate over the possible causes and implications of their
depression, thus helping to prolong the depressed mood. Indeed, less-effective
coping responses involving verbal and self-consolatory strategies have been
shown to occur more frequently in females
(Hänninen & Aro, 1996).

Neurocognitive studies have suggested that verbal strategies like
rumination may produce increased activity of the left posterior hemisphere,
whereas physical activity stimulates the right posterior hemisphere. The
tendency to activate the left hemisphere as opposed to the right hemisphere
under a variety of circumstances has been related to vulnerability to
depression. To the extent that the right hemisphere influences the
hypothalamic—pituitary—adrenal axis, physical activity may be able
to provide a normative restructuring of the axis, whose function is affected
in depression (Heller,
1993).

Social support

Poor social support is related to onset and relapse of depression either
through a direct effect unrelated to levels of concurrent adversities or
through a buffering action which adds to the effect of adversities
(Brugha, 1990). However,
levels of social support do not seem to contribute to gender differences in
depression.

It has been claimed that females have a stronger affiliative style than
males, since they require greater social support for their psychological
health. As a consequence, females may be more vulnerable to events affecting
their close emotional ties and more likely to develop depression in response
to them (‘cost of caring’ hypothesis). Contrary to expectation,
there is no evidence for the excess of depression among females being caused
by reduced social support. Research on the association between social support
and depression in males and females has provided controversial findings, with
some studies reporting that social support is equally important in males and
females as a predictor of recovery from depression, and others showing greater
beneficial effects or even a detrimental action in either of the two genders
(Bebbington, 1996).

Genetic factors

Although genetic factors retain a strong influence on liability to
depression, they do not seem to contribute to the increased risk to females by
a direct mechanism. A recent population-based twin study of life-time major
depression showed that the degree of genetic liability to depression is
similar in males and females who share most of the genetic risk factors
(Kendler & Prescott,
1999). Another study confirmed these findings for major depression
defined according to DSM-IV (American
Psychiatric Association, 1994) criteria, but not for other
definitions of major depression (Bierut
et al, 1999). On the other hand, genetic factors might
indirectly increase vulnerability to depression in one gender through
temperamental features associated with low self-esteem and reduced social
support or social integration (Kessler
et al, 1992; McGuffin
et al, 1996; Kendler
et al, 1998).

In the search for genetic factors implicated in gender differences in
depression, attention has been paid both to genes contributing to sexual
dimorphism and to genes resulting in family resemblance. No empirical evidence
has supported a link between the preponderance of females in depression and
dominant genes located on the X-chromosome
(Faraone et al,
1987). The assumption that females have lower illness thresholds
than males (threshold liability model) has received no support, since the risk
of recurrence of depressive illness seems to be independent of the proband's
gender (Merikangas et al,
1985). An alternative explanation may be that females have greater
liability to depression owing to systematic non-familial biological and/or
environmental differences, with familial transmission contributing to
variation around the means (Rice et
al, 1984).

Gonadal hormones

Gonadal hormones influence neurotransmitter functioning and circadian
rhythms through both genomic and non-genomic effects and contribute to
personality features and coping responses to stress
(Parry, 1995), but other
biological factors and environmental variables seem to be more prominent in
depression (Seeman, 1997).

A sharp increase in depression rates in females occurs usually around
mid-puberty. A direct relationship between levels of gonadal hormones and
negative affect has been reported, although the social impact of puberty, the
resulting cognitive changes and the rising levels of life stress also can be
involved. A pathogenetic role of early pubertal timing has not been confirmed
by recent studies, which showed that pubertal status was a better predictor of
the emergence of depression than the timing of pubertal transition
(Bebbington, 1996;
Angold et al, 1998;
Silberg et al, 1999).
Genetic factors influencing the risk of depression and negative life events
have been reported to interact with pubertal status and gender to produce
higher depression rates in adolescent girls, suggesting that the genetic
predisposition to depression and to stressful events may be ‘switched
on’ at puberty in females (Silberg
et al, 1999).

Other hormonal factors

Activation of the hypothalamic—pituitary—adrenal axis, impaired
negative feedback control and associated adrenal hypertrophy are mediators
(and markers) of the environmental influences on depression onset
(Checkley, 1996). The axis
seems to be more reactive to stress in females than in males, possibly due to
a modulating role of gonadal hormones
(Weiss et al, 1999).
However, contrasting findings have been reported on the proposed role of the
axis in producing gender differences in depression. Halbreich & Lumley
(1993) showed that age has a
differential effect on the increase of cortisol plasma levels in males and
females. A correlation between cortisol levels and age was detected in younger
females but not in males or post-menopausal females, suggesting that hormonal
changes during the menstrual cycle may contribute to an imbalance in plasma
levels of cortisol. On the other hand, Young
(1995) found that
post-menopausal females with recurrent depression had higher
post-dexamethasone free cortisol than pre-menopausal females with depression,
indicating that in pre-menopausal females oestrogens might limit the adverse
sequelae of hypocortisolaemia.

Another vulnerability factor relates to the function of the
hypothalamic—pituitary—thyroid axis, since about 25% of depressed
subjects show an abnormal increase of plasma levels of thyroid-stimulating
hormone after intravenous thyrotropin-releasing hormone, and autoimmune
thyroiditis and other thyroid abnormalities have been related to the onset of
depression (Whybrow, 1995).
Although disorders of this axis are more common in females than in males, they
can hardly account for the observed gender differences in depression.

Neurotransmitter systems

Gender differences have been reported in two neurotransmitter systems
traditionally implicated in the pathophysiology of depression (namely
noradrenalin and serotonin), but their role is still unclear.

The changing rate of plasma levels of 3-methoxy-4-hydroxyphenylglycol with
age may differ in males and females with depression. Whereas most females with
depression are below or above the reference range according to age, most males
with depression lie within reference ranges. By inference, an age-related
gender difference in vulnerability to dysregulation of the noradrenalin system
has been suggested (Halbreich &
Lumley, 1993). Similarly, the ageing process of some serotonin
systems might be more apparent in females than males, as measured by diurnal
variations in imipramine binding and serotonin uptake in platelets. The
likelihood of a relationship between food intake, weight gain and depressed
mood in females, with brain serotonin being involved in these disturbances of
mood and appetite, is intriguing (Wurtman,
1993).

Gender differences in depression

Although artefactual determinants may enhance a female preponderance in
depressive disorders to some extent, gender differences in depression are
genuine. Determinants of such differences are far from being established and
their combination into integrated aetio-pathogenetic models continues to be
lacking. At present, adverse experiences in childhood, depression and anxiety
disorders in childhood and adolescence, sociocultural roles with related
adverse experiences, and psychological attributes related to vulnerability to
adverse life events and coping skills are likely to be involved. Genetic and
biological factors and poor social support, however, have few or no effects in
the emergence of gender differences.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

Biological sex is an immutable socio-demographic variable not influenced by
disease and thus is a useful starting point in the investigation of risk
factors for depression.

Investigations into gender differences in depression can assess the
relative importance of risk factors from different domains, including
biological, psychological and sociocultural influences.

Clinically important risk factors for predominance of females in depression
are: sexual abuse and adverse childhood experiences; role limitation with
associated lack of choice, role overload and competing social roles;
psychological attributes related to vulnerability to life events and coping
skills.

LIMITATIONS

Few efforts have been made to combine putative risk factors for gender
differences in depression into integrated aetio-pathogenetic models because of
difficulties arising in empirical testing.

The approach based on biological sex is rarely combined with the study of
developmental processes underlying the acquisition of gender identity.

There is a relative lack of longitudinal studies testing several variables
simultaneously for their ability to predict the appearance of depressive
episodes and related gender differences.

Bracke, P. (1998) Sex differences in the course
of depression: evidence from a longitudinal study of a representative sample
of the Belgian population. Social Psychiatry and Psychiatric
Epidemiology, 33, 420
-429.

Kendler, K. S., Davis, C. G. & Kessler, R. C.
(1997) The familial aggregation of common psychiatric and
substance use disorders in the National Comorbidity Survey: a family history
study. British Journal of Psychiatry,
170, 541
-548.